Novel trifluoromethyl-oxadiazole derivatives and their use in the treatment of disease

a trifluoromethyloxadiazole and derivative technology, applied in the field of new trifluoromethyloxadiazole derivatives, can solve problems such as interference with the cell transcriptional machinery, and achieve the effects of reducing or inhibiting, reducing symptoms, and reducing side effects

Active Publication Date: 2014-11-06
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This expansion produces a mutated protein (mHTT) with a polyglutamine repeat within the amino terminus. mHTT and its proteolytic N-terminal fragments accumulate in intracellular aggregates and have been shown to interfere with the transcriptional machinery of the cell.
As SAHA is a non-selective inhibitor of all HDACs Class I, IIa+IIb and IV sub-families it is not possible to determine through which isotype / sub-family the beneficial effects are mediated.

Method used

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  • Novel trifluoromethyl-oxadiazole derivatives and their use in the treatment of disease
  • Novel trifluoromethyl-oxadiazole derivatives and their use in the treatment of disease
  • Novel trifluoromethyl-oxadiazole derivatives and their use in the treatment of disease

Examples

Experimental program
Comparison scheme
Effect test

example 1

N-(5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrazin-2-yl)acetamide

[0315]

5-Amino-N′-hydroxypyrazine-2-carboximidamide

[0316]To 2-amino-5-cyanopyrazine (Ark Pharm Inc) (4.87 g, 40.5 mmol) and hydroxylamine hydrochloride (6.20 g, 89 mmol) in EtOH (30 mL) was added triethylamine (9.44 g, 93 mmol). The reaction was stirred at 80° C. for 1 h. The precipitate was filtered, washed with a small volume ethanol and dried on high vacuum to give 6-amino-N′-hydroxypyrazine-2-carboximidamide (5.9 g, 38.5 mmol, 95% yield) as a yellow powder. HPLC RT=0.593 min (Method A), ESIMS [M+H]+=154

5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrazin-2-amine

[0317]To 5-amino-N′-hydroxypyrazine-2-carboximidamide (1.12 g, 7.31 mmol) in dry THF (6 mL) at rt was added 2,2,2-trifluoroacetic anhydride (4.61 g, 21.94 mmol). The dark-yellow solution was then heated up and stirred at reflux temperature for 16 h. Subsequently the reaction was quenched by addition of a 25 mol % ammonia solution to reach a basic pH. Brine...

example 2

4-Cyano-N-(5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrazin-2-yl)benzamide

[0319]

[0320]4-Cyano-N-(5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrazin-2-yl)benzamide was made using a process analogous to that described in Example 1 HPLC RT=3.577 min (Method A), ESIMS [M+H]+=361, light pink powder

[0321]1H NMR (400 MHz, DMSO-d6) δ ppm 11.92-11.95 (m, 1H) 9.64-9.66 (m, 1H) 9.19-9.22 (m, 1H) 8.21-8.24 (m, 1H) 8.19-8.22 (m, 1H) 8.07-8.09 (m, 1H) 8.05-8.07 (m, 1H)

example 3

N-methyl-N-(pyridin-4-ylmethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-2-amine

[0322]

2-(methyl(pyridin-4-ylmethyl)amino)pyrimidine-5-carbonitrile

[0323]To a solution of 2-(methylthio)pyrimidine-5-carbonitrile (Biofine International Inc.) (390 mg, 2.58 mmol) in 1,4-dioxane (3 mL), N-methyl-1-(pyridin-4-yl)methanamine (Fisher Scientific International—Maybridge) (789 mg, 2.50 mmol) was added at rt. The resulting reaction mixture was heated in the microwave oven at 170° C. for 10 h. Subsequently the solvent was evaporated at high vacuum and the remaining oily residue subjected to purification by flash chromatography (ISCO CombiFlash Rf; 80 g silicagel, dichlormethane / methanol) to give 2-(methyl(pyridin-4-ylmethyl)amino)pyrimidine-5-carbonitrile (404 mg, 1.65 mmol, 64% yield) as yellow powder. HPLC RT 1.323 min (Method A); ESIMS [M+1]+ 226

N′-hydroxy-2-(methyl(pyridin-4-ylmethyl)amino)pyrimidine-5-carboximidamide

[0324]To a mixture of 2-(methyl(pyridin-4-ylmethyl)amino)pyrimid...

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Abstract

The invention relates to novel trifluoromethyl-oxadiazole derivatives of formula (I), and pharmaceutically acceptable salts thereof, in which all of the variables are as defined in the specification, pharmaceutical compositions thereof, pharmaceutical combinations thereof, and their use as medicaments, particularly for the treatment of neurodegeneration, muscle atrophy or diabetes / metabolic syndrome via inhibition of HDAC4.

Description

FIELD OF THE INVENTION[0001]The invention relates to novel trifluoromethyl-oxadiazole derivatives and pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, pharmaceutical combinations thereof, and their use as medicaments, particularly for the treatment of neurodegeneration, muscle atrophy or diabetes / metabolic syndrome via inhibition of HDAC4.BACKGROUND OF THE INVENTION[0002]Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with an incidence of 1 in 10'000 (approx. 30'000 patients in USA). HD is not prevalent to any particular population, race or ethnic group, and both genders are affected. HD manifests in middle age (30-50 years) with jerking, uncontrollable movement of the limbs, trunk and face followed by progressive loss of mental abilities and development of psychiatric problems. The disease continues without remission over 10 to 25 years and is ultimately terminal.[0003]The cause of the disease is an expansion of CAG repeat...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D413/14C07D413/04A61K31/444A61K31/4439A61K31/497A61K31/506
CPCC07D413/14A61K31/497C07D413/04A61K31/444A61K31/4439A61K31/506A61P1/00A61P1/16A61P3/00A61P3/02A61P3/04A61P3/06A61P3/10A61P5/50A61P7/00A61P7/02A61P9/00A61P9/10A61P9/12A61P11/00A61P13/02A61P13/12A61P19/00A61P19/06A61P21/00A61P25/00A61P25/02A61P25/14A61P25/16A61P25/28A61P43/00
Inventor HEBACH, CHRISTINAKALLEN, JOERGNOZULAK, JOACHIMTINTELNOT-BLOMLEY, MARINAWIDLER, LEO
Owner NOVARTIS AG
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